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Graded Elevation of C-Jun in Schwann Cells in Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination

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Graded Elevation of C-Jun in Schwann Cells in Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination The Journal of Neuroscience, December 13, 2017 • 37(50):12297–12313 • 12297 Development/Plasticity/Repair Graded Elevation of c-Jun in Schwann Cells In Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination Shaline V. Fazal,1* XJose A. Gomez-Sanchez,1* Laura J. Wagstaff,1 Nicolo Musner,2 XGeorg Otto,3 Martin Janz,4 Rhona Mirsky,1 and Kristján R. Jessen1 1Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom, 2Enzo Life Sciences, 4415 Lausen, Switzerland, 3University College London Great Ormond Street Institute of Child Health, London WC1N1EH, United Kingdom, and 4Max Delbru¨ck Center for Molecular Medicine and Charite´, University Hospital Berlin, Campus Benjamin Franklin, 13092 Berlin, Germany Schwann cell c-Jun is implicated in adaptive and maladaptive functions in peripheral nerves. In injured nerves, this transcription factor promotes the repair Schwann cell phenotype and regeneration and promotes Schwann-cell-mediated neurotrophic support in models of peripheral neuropathies. However, c-Jun is associated with tumor formation in some systems, potentially suppresses myelin genes, and has been implicated in demyelinating neuropathies. To clarify these issues and to determine how c-Jun levels determine its function, we have generated c-Jun OE/ϩ and c-Jun OE/OE mice with graded expression of c-Jun in Schwann cells and examined these lines during development, in adulthood, and after injury using RNA sequencing analysis, quantitative electron microscopic morphometry, Western blotting, and functional tests. Schwann cells are remarkably tolerant of elevated c-Jun because the nerves of c-Jun OE/ϩ mice, in which c-Jun is elevated ϳ6-fold, are normal with the exception of modestly reduced myelin thickness. The stronger elevation of c-Jun in c-Jun OE/OE mice is, however, sufficient to induce significant hypomyelination pathology, implicating c-Jun as a potential player in demyeli- nating neuropathies. The tumor suppressor P19 ARF is strongly activated in the nerves of these mice and, even in aged c-Jun OE/OE mice, there is no evidence of tumors. This is consistent with the fact that tumors do not form in injured nerves, although they contain proliferating Schwann cells with strikingly elevated c-Jun. Furthermore, in crushed nerves of c-Jun OE/ϩ mice, where c-Jun levels are overexpressed sufficiently to accelerate axonal regeneration, myelination and function are restored after injury. Key words: c-Jun; myelin; PNS; regeneration; Schwann; tumorigenesis Significance Statement In injured and diseased nerves, the transcription factor c-Jun in Schwann cells is elevated and variously implicated in controlling bene- ficial or adverse functions, including trophic Schwann cell support for neurons, promotion of regeneration, tumorigenesis, and suppres- sionofmyelination.Toanalyzethefunctionsofc-Jun,wehaveusedtransgenicmicewithgradedelevationofSchwanncellc-Jun.Weshow that high c-Jun elevation is a potential pathogenic mechanism because it inhibits myelination. Conversely, we did not find a link between c-Jun elevation and tumorigenesis. Modest c-Jun elevation, which is beneficial for regeneration, is well tolerated during Schwann cell development and in the adult and is compatible with restoration of myelination and nerve function after injury. Introduction this transcription factor is a global amplifier of the repair Schwann Schwann cell c-Jun has been implicated both in adaptive and cell phenotype and promotes regeneration and, in models of pe- maladaptive functions in peripheral nerves. In injured nerves, ripheral neuropathies, Schwann cell c-Jun supports axonal sur- *S.V.F. and J.A.G.-S. contributed equally to this work. Received April 12, 2017; revised Sept. 22, 2017; accepted Oct. 8, 2017. Correspondence should be addressed to either Kristjan R. Jessen or Rhona Mirsky, Department of Cell and Author contributions: R.M. and K.R.J. designed research; S.V.F., J.A.G.-S., L.J.W., and N.M. performed research; Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom, E-mail: M.J.contributedunpublishedreagents/analytictools;S.V.F.,J.A.G.-S.,G.O.,andK.R.J.analyzeddata;R.M.andK.R.J. [email protected] or [email protected]. wrote the paper. DOI:10.1523/JNEUROSCI.0986-17.2017 This work was supported by the Wellcome Trust (Programme Grant 074665 to K.R.J. and R.M.), the Medical Copyright © 2017 Fazal, Gomez-Sanchez et al. Research Council (Project Grant G0600967 to K.R.J. and R.M.), and the European Community (Grant HEALTH-F2- This is an open-access article distributed under the terms of the Creative Commons Attribution License 2008-201535 from FP7/2007-3013). We thank M. Turmaine for providing help and advice for electron microscopy. Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in The authors declare no competing financial interests. any medium provided that the original work is properly attributed. 12298 • J. Neurosci., December 13, 2017 • 37(50):12297–12313 Fazal, Gomez-Sanchez et al. • Enforced Expression of c-Jun in Schwann Cells vival, trophic factor expression, and sensory–motor function Materials and Methods (Arthur-Farraj et al., 2012, 2017; Hantke et al., 2014; Klein et al., Transgenic mice 2014; Jessen and Mirsky, 2016). Reduced c-Jun levels in Schwann Animal experiments conformed to UK Home Office guidelines under the cells are also implicated in failure of regeneration due to aging supervision of University College London (UCL) Biological Services. To and long-term denervation (Painter et al., 2014; Jessen and Mir- generate mice that overexpress c-Jun selectively in Schwann cells, female sky, 2016). The c-Jun pathway is therefore of interest for the R26c-Junstopf mice, generated in the laboratory of Klaus Rajewsky, which carry a lox-P flanked STOP cassette in front of a CAG promoter-driven development of a pharmacology for nerve repair. Conversely, ϩ Ϫ c-Jun cDNA in the ROSA26 locus, were crossed with male P0Cre / c-Jun is associated with tumor formation in some systems and mice (Feltri et al., 1999). This generated P0-Cre ϩ/ Ϫ;R26c-Junstopf f/ϩ potentially suppresses myelin genes (Eferl and Wagner, 2003; mice, which we refer to as c-Jun OE/ϩ mice. These male mice were Parkinson et al., 2008). Based on this, it has been characterized as back-crossed with female R26c-Junstopf f/f mice to generate P0-Cre ϩ; a negative regulator of myelination and implicated in demy- R26c-Junstopf f/f mice, referred to as c-Jun OE/OE mice. P0-Cre Ϫ / Ϫ lit- elinating neuropathies (Jessen and Mirsky, 2008). In the present termates were used as controls. Mice of either sex and on the C57BL/6 work, we have generated and analyzed mouse lines with graded background were used in the experiments. expression of c-Jun in Schwann cells to clarify these issues and to determine how c-Jun levels determine its function. Genotyping DNA for genotyping was extracted from ear or tail samples using the c-Jun is present at low levels in Schwann cells of uninjured HotSHot method (Truett et al., 2000). Primers for genotyping the R26c- nerves, but is rapidly elevated 80- to 100-fold after nerve cut (De Junstopf transgene were 5Ј-TGGCACAGCTTAAGCAGAAA-3Ј and 5Ј- Felipe and Hunt, 1994; Shy et al., 1996; Parkinson et al., 2008;J. GCAATATGGTGGAAAATAAC-3Ј (270bp). The primers for the Rosa26 Gomez-Sanchez, K.R. Jessen, and R. Mirsky, unpublished data). wild-type locus were 5ЈGGAGTGTTGCAATACCTTTCTGGGAGTTC-3Ј c-Jun elevation is also seen in human neuropathies (Hutton et al., and 5ЈTGTCCCTCCAATTTTACACCTGTTCAATTC-3Ј (217bp band). 2011). Although c-Jun is implicated in the promotion of a num- The primers for the P0-Cre transgene were 5Ј-GCTGGCCCAAATGTT ber of tumors, in other situations, it may have a role in the pre- GCTGG-3Ј and 5ЈCCACCACCTCTCCATTGCAC-3Ј (480 bp band). vention of tumorigenesis by mechanisms that include activation of tumor suppressors such as P14 ARF/p19 ARFand Dmp1 (Eferl Nerve injury The sciatic nerve was exposed and crushed (3 ϫ 15 s at 3 rotation angles) and Wagner, 2003; Ameyar-Zazoua et al., 2005; Shaulian, 2010). ARF at the sciatic notch using angled forceps. The wound was closed using P19 is elevated in Schwann cells after nerve transection and veterinary autoclips. The nerve distal to the crush was excised for analysis the striking activation of Schwann cell c-Jun after injury is not at various time points. Contralateral uninjured sciatic nerves were used associated with tumor formation (Gomez-Sanchez et al., 2013; as controls for Western blotting, immunofluorescence, or electron Jessen et al., 2015b). Rather, the role of c-Jun is to take part in microscopy. controlling the conversion of myelin and Remak cells to Schwann cell specialized to perform injury-specific tasks and to promote Schwann cell culture repair (Jessen et al., 2015a; Jessen and Mirsky, 2016; Arthur- Schwann cell cultures were prepared from sciatic nerves of postnatal day 8 (P8)–P10 mouse pups essentially as in Morgan et al. (1991) and Arthur- Farraj et al., 2017; Gomez-Sanchez et al., 2017). This includes Farraj et al. (2011). After enzymatic dissociation and centrifugation, preventing the death of injured neurons and promoting axon the cell pellet was resuspended in defined medium (DM) (Meier et al., Ϫ6 growth by expression of trophic factors, guiding axons back to 1999) containing 10 M insulin and 5% horse serum (HS) and plated in their targets by forming regeneration tracks (Bungner bands), drops on coverslips coated with poly-L-lysine and laminin. Cells were and breakdown of myelin directly by autophagy and indirectly by incubated at 37°C/5% CO2 and allowed to adhere for 24 h. After 24 h, cytokine expression to recruit macrophages. Inactivation of the medium was changed to DM/0.5% HS (controls), DM with 10 Schwann cell c-Jun results in defective repair Schwann cells and ng/ml NRG1 alone, or DM with NRG1 10 ng/ml and dbcAMP 1 mM for impaired regeneration (Arthur-Farraj et al., 2012; Jessen and 48 h before fixation and immunolabeling.
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